The structure, function and distribution of G protein coupled receptors are being studied with emphasis on the cannabinoid receptors. We have created transgenic mice in which either the CB1 or CB2 cannabinoid receptor has been knocked out and are in the early stages of characterizing their phenotypes in order to gain a better understanding of the normal physiological role of these receptors and their recently discovered endogenous ligands, e.g., anandamide. In collaboration with Phil Murphy, we have identified one of our orphan receptor clones as a receptor for the CC chemokine I-309 making this receptor (CCR8) the eighth CC chemokine receptor to be identified. A number of the CC chemokine receptors, including CCR8, act as coreceptors together with CD4 for infection of cells by various strains of HIV or SIV. Thus this receptor can be expected to be important in designing drugs to block the receptors as a means of preventing HIV entry into uninfected cells. A receptor for parathyroid hormone (PTH) which also responds to a related protein, originally referred to hypercalcemia of malignancy factor but now known as PTH-related peptide (PTHrp), has been known for several years. Recently Ted Usdin and I cloned the human cDNA of a previously unsuspected second receptor which responds to PTH but not PTHrp and is expressed predominantly in brain. In order to better understand its physiological role, we have started to make transgenic mice with the receptor inactivated by deletion of a major portion of coding sequence of the gene.